RT Journal Article
SR Electronic
T1 Lipid flippase dysfunction as a novel therapeutic target for endosomal anomalies in Alzheimer’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.30.454423
DO 10.1101/2021.07.30.454423
A1 Kaneshiro, Nanaka
A1 Komai, Masato
A1 Imaoka, Ryosuke
A1 Ikeda, Atsuya
A1 Kamikubo, Yuji
A1 Hashimoto, Tadafumi
A1 Iwatsubo, Takeshi
A1 Sakurai, Takashi
A1 Uehara, Takashi
A1 Takasugi, Nobumasa
YR 2021
UL http://biorxiv.org/content/early/2021/08/29/2021.07.30.454423.abstract
AB β-amyloid precursor protein (APP) and their metabolites are deeply involved in the development of Alzheimer’s disease (AD). Upon the upregulation of β-site APP cleaving enzyme 1 (BACE1), its product, the β-carboxyl-terminal fragment of APP (βCTF), is accumulated in the early stage of sporadic AD brains. βCTF accumulation is currently considered the trigger for endosomal anomalies to form enlarged endosomes, one of the earliest pathologies in AD. However, the details of the underlying mechanism remain largely unclear. In this study, using BACE1 stably-overexpressing cells, we describe that lipid flippase subcomponent TMEM30A interacts with accumulated βCTF. Among the lipid flippases in endosomes, those composed of TMEM30A and active subcomponent ATP8A1 transports phospholipid, phosphatidylserine (PS), to the cytosolic side of the endosomes. The lipid flippase activity and cytosolic PS distribution are critical for membrane fission and vesicle transport. Intriguingly, accumulated βCTF in model cells impaired lipid flippase physiological formation and activity, along with endosome enlargement. Moreover, in the brains of AD model mice before the amyloid-β (Aβ) deposition, the TMEM30A/βCTF complex formation occurred, followed by lipid flippase dysfunction. Importantly, our novel Aβ/βCTF interacting TMEM30A-derived peptide “T-RAP” improved endosome enlargement and reduced βCTF levels. These T-RAP effects could result from the recovery of lipid flippase activity. Therefore, we propose lipid flippase dysfunction as a key pathogenic event and a novel therapeutic target for AD.Competing Interest StatementThe authors have declared no competing interest.